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1.
Drug Alcohol Depend ; 217: 108327, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33091843

RESUMO

The severity of the overdose epidemic underscores the urgent need for innovative and high impact interventions that promote the rapid penetration and scale up of evidence-based practices (EBPs) in communities profoundly affected by fatal opioid overdose. This special issue shares scientific advancements in implementation research design and evaluation of a novel data-driven community-based intervention. The HEALing (Helping End Addiction Long-Term) Communities Study (HCS) is a four-year study that is designed to examine the effectiveness of the Communities That HEAL (CTH) intervention. The CTH intervention supports the dissemination of EBPs in 67 communities across four high-burdened states-Kentucky, Massachusetts, New York, and Ohio. The diversity in these communities in terms of rural-urban status, race-ethnicity and other social determinants of health facilitates generalizability of results to other communities across the US. The nine papers in this special issue describe critical elements that constitute the HCS framework and design. This includes the implementation of EBPs that have a substantial impact on fatal and non-fatal opioid overdose, the Opioid-overdose Reduction Continuum of Care Approach, communication campaigns to increase awareness and demand for EBPs and reduce stigma against people with OUD and MOUD interventions, and the process of community engagement. This includes how to form community coalitions and gain their commitment, and steps taken to mobilize coalitions to pursue EBP implementation and ensure EBPs are adapted for community needs. The collective papers in this issue demonstrate that the design of any complex study must adapt to unanticipated temporal events, including the rapidly emerging COVID-19 crisis. Readers will learn about the scientific process of the design and implementation of a community-engaged intervention, its methodologies, guiding conceptual models, and research implementation strategies that can be applied to address other health issues.

2.
JAMA Intern Med ; 180(9): 1232-1240, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32730575

RESUMO

Importance: Repeated bone mineral density (BMD) testing to screen for osteoporosis requires resources. For patient counseling and optimal resource use, it is important for clinicians to know whether repeated BMD measurement (compared with baseline BMD measurement alone) improves the ability to discriminate between postmenopausal women who will and will not experience a fracture. Objective: To assess whether a second BMD measurement approximately 3 years after the initial assessment is associated with improved ability to estimate fracture risk beyond the baseline BMD measurement alone. Design, Setting, and Participants: The Women's Health Initiative is a prospective observational study. Participants in the present cohort study included 7419 women with a mean (SD) follow-up of 12.1 (3.4) years between 1993 and 2010 at 3 US clinical centers. Data analysis was conducted between May 2019 and December 2019. Main Outcomes and Measures: Incident major osteoporotic fracture (ie, hip, clinical spine, forearm, or shoulder fracture), hip fracture, baseline BMD, and absolute change in BMD were assessed. The area under the receiver operating characteristic curve (AU-ROC) for baseline BMD, absolute change in BMD, and the combination of baseline BMD and change in BMD were calculated to assess incident fracture risk discrimination during follow-up. Results: Of 7419 participants, the mean (SD) age at baseline was 66.1 (7.2) years, the mean (SD) body mass index was 28.7 (6.0), and 1720 (23%) were nonwhite individuals. During the study follow-up (mean [SD] 9.0 [3.5] years after the second BMD measurement), 139 women (1.9%) experienced hip fractures, and 732 women (9.9%) experienced major osteoporotic fracture. In discriminating between women who experience hip fractures and those who do not, AU-ROC values were 0.71 (95% CI, 0.67-0.75) for baseline total hip BMD, 0.61 (95% CI, 0.56-0.65) for change in total hip BMD, and 0.73 (95% CI, 0.69-0.77) for the combination of baseline total hip BMD and change in total hip BMD. Femoral neck and lumbar spine BMD values had similar discrimination for hip fracture. For discrimination of major osteoporotic fracture, AU-ROC values were 0.61 (95% CI, 0.59-0.63) for baseline total hip BMD, 0.53 (95% CI, 0.51-0.55) for change in total hip BMD, and 0.61 (95% CI, 0.59-0.63) for the combination of baseline total hip BMD and change in total hip BMD. Femoral neck and lumbar spine BMD values had similar ability to discriminate between women who experienced major osteoporotic fracture and those who did not. Associations between change in bone density and fracture risk did not differ by subgroup, including diabetes, age, race/ethnicity, body mass index, or baseline BMD T score. Conclusions and Relevance: The findings of this study suggest that a second BMD assessment approximately 3 years after the initial measurement was not associated with improved discrimination between women who did and did not experience subsequent hip fracture or major osteoporotic fracture beyond the baseline BMD value alone and should not routinely be performed.

4.
Oncologist ; 25(8): 712-721, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32250503

RESUMO

BACKGROUND: Recent clinical trials have evaluated angiotensin-converting enzyme (ACE) inhibitors (ACEis), angiotensin receptor blockers (ARBs), and beta blockers (BBs) in relation to cardiotoxicity in patients with cancer, typically defined by ejection fraction declines. However, these trials have not examined long-term, hard clinical endpoints. Within a prospective study, we examined the risk of heart failure (HF) and coronary heart disease (CHD) events in relation to use of commonly used antihypertensive medications, including ACEis/ARBs, BBs, calcium channel blockers (CCB), and diuretics, comparing women with and without cancer. MATERIALS AND METHODS: In a cohort of 56,997 Women's Health Initiative study participants free of cardiovascular disease who received antihypertensive treatment, we used multivariable-adjusted Cox regression models to calculate the hazard ratios (HRs) of developing CHD, HF, and a composite outcome of cardiac events (combining CHD and HF) in relation to use of ACEis/ARBs, CCBs, or diuretics versus BBs, separately in women with and without cancer. RESULTS: Whereas there was no difference in risk of cardiac events comparing ACEi/ARB with BB use among cancer-free women (HR = 0.99 [0.88-1.12]), among cancer survivors ACEi/ARB users were at a 2.24-fold risk of total cardiac events (1.18-4.24); p-interaction = .06). When investigated in relation to CHD only, an increased risk was similarly observed in ACEi/ARB versus BB use for cancer survivors (HR = 1.87 [0.88-3.95]) but not in cancer-free women (HR = 0.91 [0.79-1.06]; p-interaction = .04). A similar pattern was also seen in relation to HF but did not reach statistical significance (p-interaction = .23). CONCLUSION: These results from this observational study suggest differing risks of cardiac events in relation to antihypertensive medications depending on history of cancer. Although these results require replication before becoming actionable in a clinical setting, they suggest the need for more rigorous examination of the effect of antihypertensive choice on long-term cardiac outcomes in cancer survivors. IMPLICATIONS FOR PRACTICE: Although additional research is needed to replicate these findings, these data from a large, nationally representative sample of postmenopausal women indicate that beta blockers are favorable to angiotensin-converting enzyme inhibitors in reducing the risk of cardiac events among cancer survivors. This differs from the patterns observed in a noncancer cohort, which largely mirrors what is found in the randomized clinical trials in the general population.

6.
J Foot Ankle Res ; 13(1): 11, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131869

RESUMO

BACKGROUND: Hallux valgus, one of the most common structural foot deformities, is highly heritable. However, previous efforts to elucidate the genetic underpinnings of hallux valgus through a genome-wide association study (GWAS) conducted in 4409 Caucasians did not identify genome-wide significant associations with hallux valgus in both gender-specific and sex-combined GWAS meta-analyses. In this analysis, we add newly available data and more densely imputed genotypes to identify novel genetic variants associated with hallux valgus. METHODS: A total of 5925 individuals of European Ancestry were categorized into two groups: 'hallux valgus present' (n = 2314) or 'no deformity' (n = 3611) as determined by trained examiners or using the Manchester grading scale. Genotyping was performed using commercially available arrays followed by imputation to the Haplotype Reference Consortium (HRC) reference panel version 1.1. We conducted both sex-specific and sex-combined association analyses using logistic regression and generalized estimating equations as appropriate in each cohort. Results were then combined in a fixed-effects inverse-variance meta-analyses. Functional Mapping and Annotation web-based platform (FUMA) was used for positional mapping, gene and gene-set analyses. RESULTS: We identified a novel locus in the intronic region of CLCA2 on chromosome 1, rs55807512 (OR = 0.48, p = 2.96E-09), an expression quantitative trait locus for COL24A1, a member of the collagen gene family. CONCLUSION: In this report of the largest GWAS of hallux valgus to date, we identified a novel genome-wide significant locus for hallux valgus. Additional replication and functional follow-up will be needed to determine the functional role of this locus in hallux valgus biology.

7.
Gait Posture ; 77: 175-181, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32044697

RESUMO

BACKGROUND: Suboptimal patient-reported function and movement impairments often persist after hip arthroscopy for femoroacetabular impingement syndrome (FAIS). Individuals with FAIS with preoperative cartilage pathology (ie. chondropathy) demonstrate distinct movement patterns and have worse post-operative outcomes. It is unknown whether the presence of chondropathy after surgery negatively affects movement and function. RESEARCH QUESTION: Do sagittal plane gait mechanics differ based on chondropathy severity following arthroscopy for FAIS? METHODS: A cross-sectional walking gait analysis was performed for 25 participants post-arthroscopy (2.48 ±â€¯1.38y) and 12 healthy controls (HCs). Peak total support moment (TSM) and relative contributions of the hip, knee, and ankle were calculated during loading response. The Hip Osteoarthritis MRI Scoring System was used to categorize the FAIS group into no-mild or moderate-severe chondropathy groups based on 3 T magnetic resonance imaging of their surgical hip. The interactions of group by limb were evaluated for kinetic variables, covaried by gait speed. RESULTS: Groups did not differ based on age, BMI and sex distribution (P ≥ 0.14). 13 participants with FAIS presented with moderate-severe chondropathy and 12 presented with no-mild chondropathy. Participants with moderate-severe chondropathy walked significantly slower than both other groups (P = 0.006) and demonstrated lower peak TSM than those with no-mild chondropathy (P = 0.002). Participants with no-mild chondropathy demonstrated lower hip (61.5 %) and greater ankle (17.7 %) contributions to the TSM on the involved limb compared to the moderate-severe group (hip:73.4 %, P = 0.07; ankle:10.5 %, P = 0.007). SIGNIFICANCE: Slower gait speed alone did not explain the lower TSM strategy in participants with moderate-severe chondropathy. Interestingly, the joint contribution strategy of this group was not different than HCs. Participants with no-mild chondropathy demonstrated a TSM strategy that shifted the demand away from their hip and toward their ankle. Given the small sample size, and large variability in joint strategies, future work needs to examine whether these alterations in gait strategy, with or without advanced chondropathy, impact patient function.


Assuntos
Artroscopia , Cartilagem Articular/patologia , Impacto Femoroacetabular/cirurgia , Marcha/fisiologia , Adolescente , Adulto , Fenômenos Biomecânicos , Cartilagem Articular/fisiopatologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Impacto Femoroacetabular/patologia , Impacto Femoroacetabular/fisiopatologia , Articulação do Quadril/patologia , Articulação do Quadril/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
8.
Bone ; 134: 115222, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31911206

RESUMO

Etidronate is a non-nitrogen-containing bisphosphonate. Because it binds with calcium and inhibits crystal formation and dissolution, it was considered by Procter & Gamble as an additive to toothpaste (to prevent build-up of tartar) and detergent (to bind calcium and increase sudsing in "hard" water). The first clinical use (1968) was for fibrodysplasia ossificans progressiva. The first approved clinical use (1977) was for treatment of Paget's disease of bone. Other approved indications are hypercalcemia of malignancy and heterotopic ossification, with a host of off-label uses (including fibrous dysplasia, periodontal disease, multiple myeloma, neuropathic arthropathy, pulmonary microlithiasis, diabetic retinopathy, bone metastases, melorheostosis, urinary stone disease, periodontal disease, etc.). Unique among bisphosphonates, etidronate (oral therapy) results in hyperphosphatemia, increased tubular reabsorption of phosphorus and increased levels of 1,25-dihydroxyvitamin D. The dose that reduces bone resorption is close to the dose that impairs mineralization; prolonged high-dose use can result in osteomalacia and bone fractures. Intermittent cyclic etidronate for osteoporosis resulted in favorable changes in bone density and histomorphometry (no mineralization defect) as well as a decrease in vertebral fracture rates in postmenopausal women with osteoporosis. Later studies showed similar effects in men with osteoporosis and patients with glucocorticoid-induced osteoporosis. Although its use for osteoporosis has given way to newer bisphosphonates and other agents, because of its unique properties, it remains the bisphosphonate of choice for treatment of heterotopic ossification.

10.
Med Sci Sports Exerc ; 52(4): 795-800, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31652246

RESUMO

INTRODUCTION: Male youth in the United States commonly participate in gridiron (American) football. There are little data substantiating current popular opinion that it is associated with knee pain or osteoarthritis (OA) later in life. We aimed to evaluate the relationship of football with these outcomes in the Osteoarthritis Initiative (OAI). METHODS: This is a study of male OAI participants with knee x-ray readings, symptom assessments, and completed surveys on lifetime physical activity. The OAI is a multicenter, observational cohort recruited from the community not based on football participation status. A history of exposure to American football was ascertained via self-report. Knee radiographs were scored for Kellgren-Lawrence grade (0-4). Radiographic OA (ROA) was defined as Kellgren-Lawrence ≥ 2 in at least one knee. Frequent knee pain meant at least one knee with frequent knee pain. Symptomatic ROA required at least one knee with both ROA and frequent knee pain. RESULTS: A total of 1166 men had a mean age of 63.7 (SD, 9.2) yr and body mass index of 28.6 (SD, 4.2) kg·m. Thirty-one percent (365/1166) played football at some point in their lives, 95% of whom participated from ages 12 to 18 yr. The ORs for symptomatic ROA from the lowest to highest football participation were 1.2, 1.5, and 2.2, respectively (P for trend = 0.004). Findings were similar for football from ages 12 to 18 yr and for outcomes of knee pain and ROA. CONCLUSION: This is the first large epidemiologic study to suggest that football participation, including in the teen years, may be detrimental toward knee health. Prospective studies evaluating football players are warranted.

11.
Hum Mol Genet ; 29(1): 70-79, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31600786

RESUMO

We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10-13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10-12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

12.
Pediatrics ; 144(6)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31744891

RESUMO

OBJECTIVES: To evaluate the longitudinal effects of metabolic and bariatric surgery (MBS) on the prevalence of musculoskeletal and lower extremity (LE) pain, physical function, and health-related quality of life. METHODS: The Teen Longitudinal Assessment of Bariatric Surgery study (NCT00474318) prospectively collected data on 242 adolescents undergoing MBS at 5 centers over a 3-year follow-up. Joint pain and physical function outcomes were assessed by using the Health Assessment Questionnaire Disability Index, Impact of Weight on Quality of Life - Kids, and the Short Form 36 Health Survey. Adolescents with Blount disease (n = 9) were excluded. RESULTS: Prevalent musculoskeletal and LE pain were reduced by 40% within 12 months and persisted over 3 years. Adjusted models revealed a 6% lower odds of having musculoskeletal pain (odds ratio = 0.94, 95% confidence interval: 0.92-0.99) and a 10% lower odds of having LE pain (odds ratio = 0.90, 95% confidence interval: 0.86-0.95) per 10% reduction of BMI. The prevalence of poor physical function (Health Assessment Questionnaire Disability Index score >0) declined from 49% to <20% at 6 months (P < .05), Physical comfort and the physical component scores, measured by the Impact of Weight on Quality of Life - Kids and the Short Form 36 Health Survey, improved at 6 months postsurgery and beyond (P < .01). Poor physical function predicted persistent joint pain after MBS. CONCLUSIONS: Joint pain, impaired physical function, and impaired health-related quality of life significantly improve after MBS. These benefits in patient-reported outcomes support the use of MBS in adolescents with severe obesity and musculoskeletal pain and suggest that MBS in adolescence may reverse and reduce multiple risk factors for future joint disease.


Assuntos
Cirurgia Bariátrica/psicologia , Cirurgia Bariátrica/tendências , Exercício Físico/psicologia , Dor Musculoesquelética/diagnóstico , Dor Musculoesquelética/psicologia , Qualidade de Vida/psicologia , Adolescente , Cirurgia Bariátrica/efeitos adversos , Estudos de Coortes , Exercício Físico/fisiologia , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Obesidade Mórbida/psicologia , Obesidade Mórbida/cirurgia , Estudos Prospectivos
13.
PM R ; 2019 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-31628825

RESUMO

BACKGROUND: To date, there have not been any epidemiologic studies that have evaluated the association between swimming over a lifetime and knee health. OBJECTIVE: The study aimed to evaluate the relationship of a history of swimming with knee pain, radiographic knee OA (ROA), and symptomatic knee OA (SOA). DESIGN: Cross-sectional retrospective study. SETTING: Four academic centers in the United States. PARTICIPANTS: Respondents to the historical physical activity survey within the Osteoarthritis Initiative with knee radiographs and symptom assessments. METHODS: In this retrospective study nested within the Osteoarthritis Initiative, researchers performed logistic regression with the predictor being swimming over a lifetime and over particular age ranges. MAIN OUTCOME MEASUREMENTS: Person-based definitions of frequent knee pain, ROA, and SOA. RESULTS: A total of 2637 participants were included, with a mean age of 64.3 years (SD 8.9), body mass index of 28.4 kg/m2 (SD 4.9), and 44.2% male. Over a lifetime, the adjusted prevalence measures for frequent knee pain, ROA, and SOA for any versus no history of swimming were 36.4% (33.4% - 39.5%) v. 39.9% (37.4% - 42.5%), 54.3% (51.0% - 57.6%) v. 61.1% (58.4% - 63.7%), and 21.9% (19.4% - 24.7%) v. 27.0% (24.7% - 29.4%) respectively. CONCLUSIONS: This is the first epidemiologic study to indicate that swimming is potentially beneficial toward knee health, particularly when performed earlier in life (before age 35). Future prospective studies are needed to confirm these findings and to better scrutinize the associations in older age groups.

14.
JAMA Netw Open ; 2(10): e1914084, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31651972

RESUMO

Importance: Physical activity is inversely associated with hip fracture risk in older women. However, the association of physical activity with fracture at other sites and the role of sedentary behavior remain unclear. Objective: To assess the associations of physical activity and sedentary behavior with fracture incidence among postmenopausal women. Design, Setting, and Participants: The Women's Health Initiative prospective cohort study enrolled 77 206 postmenopausal women aged 50 to 79 years between October 1993 and December 1998 at 40 US clinical centers. Participants were observed for outcomes through September 2015, with data analysis conducted from June 2017 to August 2019. Exposures: Self-reported physical activity and sedentary time. Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs for total and site-specific fracture incidence. Results: During a mean (SD) follow-up period of 14.0 (5.2) years among 77 206 women (mean [SD] age, 63.4 [7.3] years; 66 072 [85.6%] white), 25 516 (33.1%) reported a first incident fracture. Total physical activity was inversely associated with the multivariable-adjusted risk of hip fracture (>17.7 metabolic equivalent [MET] h/wk vs none: HR, 0.82; 95% CI, 0.72-0.95; P for trend < .001). Inverse associations with hip fracture were also observed for walking (>7.5 MET h/wk vs none: HR, 0.88; 95% CI, 0.78-0.98; P for trend = .01), mild activity (HR, 0.82; 95% CI, 0.73-0.93; P for trend = .003), moderate to vigorous activity (HR, 0.88; 95% CI, 0.81-0.96; P for trend = .002), and yard work (HR, 0.90; 95% CI, 0.82-0.99; P for trend = .04). Total activity was positively associated with knee fracture (>17.7 MET h/wk vs none: HR, 1.26; 95% CI, 1.05-1.50; P for trend = .08). Mild activity was associated with lower risks of clinical vertebral fracture (HR, 0.87; 95% CI, 0.78-0.96; P for trend = .006) and total fractures (HR, 0.91; 95% CI, 0.87-0.94; P for trend < .001). Moderate to vigorous activity was positively associated with wrist or forearm fracture (HR, 1.09; 95% CI, 1.03-1.15; P for trend = .004). After controlling for covariates and total physical activity, sedentary time was positively associated with total fracture risk (>9.5 h/d vs <6.5 h/d: HR, 1.04; 95% CI, 1.01-1.07; P for trend = .01). When analyzed jointly, higher total activity mitigated some of the total fracture risk associated with sedentary behavior. Analysis of time-varying exposures resulted in somewhat stronger associations for total physical activity, whereas those for sedentary time were materially unchanged. Conclusions and Relevance: In older ambulatory women, higher total physical activity was associated with lower total and hip fracture risk but higher knee fracture risk. Mild activity and walking were associated with lower hip fracture risk, a finding with important public health implications because these activities are common in older adults. The positive association between sedentary time and total fracture risk requires further investigation.

15.
Commun Biol ; 2: 321, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31482140

RESUMO

Knee pain is one of the most common musculoskeletal complaints that brings people to medical attention. Approximately 50% of individuals over the age of 50 report an experience of knee pain within the past 12 months. We sought to identify the genetic variants associated with knee pain in 171,516 subjects from the UK Biobank cohort and seek supporting evidence in cohorts from 23andMe, the Osteoarthritis Initiative, and the Johnston County Osteoarthritis Project. We identified two loci that reached genome-wide significance in the UK Biobank: rs143384, located in GDF5 (P = 1.32 × 10-12), a gene previously implicated in osteoarthritis; and rs2808772, located near COL27A1 (P = 1.49 × 10-8). These findings were supported in cohorts with self-reported osteoarthritis/radiographic knee osteoarthritis without pain information. In this report on genome-wide association of knee pain, we identified two loci in or near GDF5 and COL27A1 that are associated with knee pain.


Assuntos
Bancos de Espécimes Biológicos , Colágenos Fibrilares/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fator 5 de Diferenciação de Crescimento/genética , Articulação do Joelho/patologia , Dor/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Regulação da Expressão Gênica , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Reino Unido
16.
Blood ; 134(19): 1645-1657, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31420334

RESUMO

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.


Assuntos
Predisposição Genética para Doença/genética , Tromboembolia Venosa/genética , Estudo de Associação Genômica Ampla , Humanos
17.
Am J Epidemiol ; 188(11): 1932-1943, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31364705

RESUMO

We identified plasma metabolites associated with habitual physical activity among 5,197 US participants from the Nurses' Health Study (NHS), Nurses' Health Study II (NHS II), and the Health Professionals Follow-up Study (HPFS). Physical activity was assessed every 2-4 years via self-report questionnaires. Blood was collected in the NHS in 1989-1990, in NHS II during 1996-1999, and in the HPFS during 1993-1995. Metabolic profiling was conducted by liquid chromatography-mass spectrometry. Our study included 337 known metabolites, with 256 of them classified as lipids. We corrected for multiple testing by controlling the tail probability of the proportion of false positives (TPPFP) and accounted for correlated tests using bootstrapping. Physical activity was significantly associated with 20 metabolites after correction for multiple testing (TPPFP < 0.05), and positive associations were found for most of the metabolites, including 2 amino acids (citrulline and glycine), 4 cholesteryl esters (C18:2, C18:1, C16:0, C18:3), 8 phosphocholines (PCs) (C36:4 PC-A, C34:3 PC plasmalogen, C36:3 PC plasmalogen, C34:2 PC plasmalogen, C36:2 PC) and lysophosphatidylcholines (C18:2, C20:5, C18:1), and 3 phosphatidylethanolamines (PEs) (C38:3 PE plasmalogen) and lysophosphatidylethanolamines (C18:2, C18:1). We independently replicated the 20 metabolites among 2,305 women in the Women's Health Initiative using 1993 data, and half of the metabolites were replicated. Our study may help identify biomarkers of physical activity and provide insight into biological mechanisms underlying the beneficial effect of being physically active on cardiometabolic health.


Assuntos
Exercício Físico/fisiologia , Metabolismo dos Lipídeos , Metaboloma , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Epidemiologia Molecular
18.
Circ Cardiovasc Qual Outcomes ; 12(4): e005284, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30909729

RESUMO

BACKGROUND: Empirical data on the link between stress and cardiovascular disease (CVD) risk among black women is limited. We examined associations of stressful life events and social strain with incident CVD among black women and tested for effect modification by resilience. METHODS AND RESULTS: Our analysis included 10 785 black women enrolled in the Women's Health Initiative Observational Study and Clinical Trials cohort. Participants were followed for CVD for up to 23 years (mean, 12.5). Multivariable Cox regression was used to estimate hazard ratios and 95% CIs for associations between stress-related exposures and incident CVD. We included interactions between follow-up time (age) and stressful life events because of evidence of nonproportional hazards. Effect modification by resilience was examined in the sub-cohort of 2765 women with resilience and stressful life events measures. Higher stressful life events were associated with incident CVD at ages 55 (hazard ratio for highest versus lowest quartile=1.80; 95% CI, 1.27-2.54) and 65 (hazard ratio for highest versus lowest quartile=1.40; 95% CI, 1.16-1.68), but not at older ages. Adjustment for CVD risk factors attenuated these associations. Similar associations were observed for social strain. In the sub-cohort of women with updated stressful life events and resilience measures, higher stressful life events were associated with incident CVD in multivariable-adjusted models (hazard ratio=1.61; 95% CI, 1.04-2.51). Resilience did not modify this association nor was resilience independently associated with incident CVD. CONCLUSIONS: In this cohort of older black women, recent reports of stressful life events were related to incident CVD. Resilience was unrelated to incident CVD. CLINICAL TRIALS REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00000611.


Assuntos
Afro-Americanos/psicologia , Doenças Cardiovasculares/etnologia , Resiliência Psicológica , Estresse Psicológico/etnologia , Saúde da Mulher/etnologia , Fatores Etários , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/psicologia , Feminino , Humanos , Incidência , Acontecimentos que Mudam a Vida , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Medição de Risco , Gestão de Riscos , Fatores Sexuais , Comportamento Social , Estresse Psicológico/diagnóstico , Estresse Psicológico/psicologia , Fatores de Tempo , Estados Unidos/epidemiologia
19.
Am J Prev Med ; 56(5): 664-672, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30902564

RESUMO

INTRODUCTION: Physical activity guidelines recommend minimum thresholds. This study sought to identify evidence-based thresholds to maintain disability-free status over 4years among adults with lower extremity joint symptoms. METHODS: Prospective multisite Osteoarthritis Initiative accelerometer monitoring cohort data from September 2008 through December 2014 were analyzed. Adults (n=1,564) aged ≥49years at elevated disability risk because of lower extremity joint symptoms were analyzed for biennial assessments of disability-free status from gait speed ≥1meter/second (mobility disability-free) and self-report of no limitations in activities of daily living (activities of daily living disability-free). Classification tree analyses conducted in 2017-2018 identified optimal thresholds across candidate activity intensities (sedentary, light, moderate-vigorous, total light and moderate-vigorous activity, and moderate-vigorous accrued in bouts lasting ≥10 minutes). RESULTS: Minimal thresholds of 56 and 55 moderate-vigorous minutes/week best predicted disability-free status over 4years from mobility and activities of daily living disabilities, respectively, across the candidate measures. Thresholds were consistent across sex, BMI, age, and knee osteoarthritis presence. Mobility disability onset was one eighth as frequent (3% vs 24%, RR=0.14, 95% CI=0.09, 0.20) and activities of daily living disability onset was almost half (12% vs 23%, RR=0.55, 95% CI=0.44, 0.70) among people above versus below the minimum threshold. CONCLUSIONS: Attaining an evidence-based threshold of approximately 1-hour moderate-vigorous activity/week significantly increased the likelihood of maintaining disability-free status over 4years. This minimum threshold tied to maintaining independent living abilities has value as an intermediate goal to motivate adults to take action towards the many health benefits of a physically active lifestyle.

20.
J Bone Miner Res ; 34(3): 464-474, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30461066

RESUMO

Sleep disturbances are common and may influence falls and fracture directly by influencing bone turnover and muscle strength or indirectly through high comorbidity or poor physical function. To investigate the association between self-reported sleep and falls and fractures, we prospectively studied 157,306 women in the Women's Health Initiative (WHI) using information on sleep quality, sleep duration, and insomnia from questionnaires. Annual self-report of falling two or more times (ie, "recurrent falling") during each year of follow-up was modeled with repeated measures logistic regression models fit by generalized estimating equations. Cox proportional hazards models were used to investigate sleep disturbance and time to first fracture. We examined the risks of recurrent falls and fracture by sleep duration with 7 hours as referent. We examined the risks across categories of sleep disturbance, insomnia status, and sleep quality. The average follow-up time was 7.6 years for falls and 12.0 years for fractures. In multivariable adjusted models, including adjustment for comorbidity, medications, and physical function, women who were short (≤5 hours) and long (≥10 hours) sleepers had increased odds of recurrent falls (odds ratio [OR] 1.28; 95% confidence interval [CI], 1.23 to 1.34 and OR 1.25; 95% CI, 1.09 to 1.43, respectively). Poor sleep quality, insomnia, and more sleep disturbances were also associated with an increased odds of recurrent falls. Short sleep was associated with an increased risk of all fractures, and upper limb, lower limb, and central body fractures, but not hip fractures, with hazard ratios ranging from 1.10 to 1.13 (p < 0.05). There was little association between other sleep characteristics and fracture. In conclusion, short and long sleep duration and poor sleep quality were independently associated with increased odds of recurrent falls. Short sleep was associated with modest increase in fractures. Future long-term trials of sleep interventions should include falls and fractures as endpoints. © 2018 American Society for Bone and Mineral Research.

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